Intramolecular aminopalladation

Unlike the intermolecular reaction, the intramolecular aminopalladation proceeds more easily[13,14,166], Methylindole (164) is obtained by the intramolecular exo amination of 2-allylaniline (163). If there is another olefinic bond in the same molecule, the aminopalladation product 165 undergoes intramolecular alkene insertion to give the tricyclic compound 166[178]. 2,2-Dimethyl-l,2-dihydroquinoline (168) is obtained by endo cyclization of 2-(3,3-dimethyiallyl)aniline (167). The oxidative amination proceeds smoothly... 

The intermediate 190 of the intramolecular aminopalladation of an allenic bond with jV-tosylcarbamate undergoes insertion of allylic chloride. Subsequent elimination of PdCl2 occurs to afford the 1,4-diene system 191. The regeneration of Pd(II) species makes the reaction catalytic without using a reoxidant[190]. 

An example of an intramolecular palladium-catalyzed oxidation of an allene involving carbonylation was used in the synthesis of pumilotoxin 251 D (equation 32)65. Intramolecular aminopalladation of the allene followed by carbonylation of the palladium-carbon bond and subsequent oxidative cleavage of the acylpalladium intermediate by CuCE afforded pyrrolidine 72 in which the chirality at the carbon at the 2-position was established. 

A Pd(II)-catalyzed sequential cyclization-coupling reaction of allenyl N-tosylcar-bamates and acrolein has been developed (Scheme 16.97) [103]. The proposed mechanism involves intramolecular aminopalladation of an allene, followed by insertion of acrolein and carbon-Pd bond protonolysis. 

Narasaka has utilized a Heck-type intramolecular aminopalladation of the olefinic moiety of r,5-unsaturated ketone 0-pentafluorobenzoyloximes 9 to afford 2,5-disubstituted pyrroles 10 (R = CH3, C02Et) <99CL45>. The use of the O-pentafluorobenzoyl group was found necessary to preclude competing Beckmann rearrangements. 

Intramolecular aminopalladation has been applied to the total synthesis of the complex skeleton of bukittinggine (179). For this reaction. Pd(CF3CO )2 (10 mol%) and benzoquinone (1.1 equiv.) are used. It is important to use freshly recrystallized benzoquinone for successful cyclization. Formation of a 7r-allylpalladium species as an intermediate in this amination reaction has been suggested 182]. The amino group in obromoaniline reacts first with acrylate in the presence of PdCF to give 180, and then intramolecular Heck reaction of the resulting alkene 180 with Pd(0) catalyst affords indolecarboxylate 181[183]. 

The usefulness of Pd-catalysed reactions is demonstrated amply in the total synthesis of clavicipitic acid [76]. The first step is intramolecular aminopalladation of the 2-vinyltosylamide 92 with Pd(II) to give the indole 93. Then stepwise Heck reactions of the iodide and bromide of 94 with two different alkenes 95 and 96 in the absence and presence of a phosphine ligand give 97. In the last step of the synthesis, the intramolecular aminopalladation of 97 with a catalytic amount of Pd(II) gives the cyclized product 99. It should be noted that the aminopalladation is a stoichiometric... 

Vinyl-substituted 2-oxazolidinones 208 were synthesised by a catalytic <02JOC974> and also asymmetric intramolecular aminopalladation of readily available derivatives of (Z)-2-buten-l,4-diol 207 <02JA12>. 

In these reactions, the nitrogen nucleophile is typically an amide, carbamate, or sulfonamide. Because of the low nucleophilicity of such nitrogen functions, no intermolecular 1,4-addition involving C—N bond formation is known. In all cases reported, the carbon-nitrogen coupling takes place in an intramolecular aminopalladation. 

As described in Section 4.1. (Scheme 29), in the frequently reviewed synthesis of N-acetyl ( )-clavicipitic acid methyl ester (167) by Hegedus [80, 81], intramolecular aminopalladation of 164 was accomplished by a Pd(n)-catalyzed process lo give the tricyclic azepinoindole 16S. 

Intramolecular aminopalladation of alkenes as a key step to pyrrolidines and related heterocycles 07CSR1142. 

Intramolecular reaction of allenes is known to proceed mainly by palladation at the central carbon to generate alkenylpalladium 235, which undergoes further reactions. Also TT-allylpalladium 236 is formed when a nucleophile attacks the central carbon. The intramolecular aminopalladation of the 6-aminoallene 237, followed by CO insertion, afforded the unsaturated amino ester 238. The reaction has been applied to the enantioselective synthesis of pumiliotoxin [103]. Oxycarbonylation of the allenyl alcohol 239 afforded the unsaturated ester 240 in 83 % yield using a catalytic amount of PdCl2 and 3 equivalents of CuCb in MeOH and is used for the synthesis of rhopaloic acid [104]. 

The same group also recently [25] developed a Pd(II)-catalyzed intramolecular aminopalladation/C-H activation sequence to synthesize pyrrolo[l,2-a]indoles of the type 77 from alkyne 76 (Scheme 3.20). 

In a recent variant on this process reported by Michael [16], a palladium(ll)-mediated intramolecular aminopalladation is followed by an oxidation of the palladium(ll) intermediate by the FN(S02Ph)2 oxidant to give a palladium(lV) complex. The palladium(lV) complex then mediates an intermolecular electrophilic aromatic substitution followed by C-C bond formation via reductive elimination (Scheme 9). 

Intramolecular aminopalladations constitute a particularly versatile approach to the generation of alkyl palladium intermediates [12]. These compounds were reacted... 

Michael recently described aminochlorination reactions from intramolecular aminopalladation follotved by reaction tvith N-chlorosuccinamide (NCS) [17]. Initial reactions made use of Michael s earlier observation on stabilization of aminopallada-tion intermediates starting from 5 mol% ligated Pd complex A [18], but further tvork shotved that simple palladium salts such as Pd(NCMe)2Cl2 could also be employed, albeit in higher catalyst loadings of 10 mol% (Eq. (4.7)). The reaction tvorks well for a series of amides and carbamates, but not for tosylates. 

The stereochemistry of aminopalladation, as is involved in the initial step of the aza-Wacker reaction, is still a subject of ongoing research. A particularly extensive mechanistic study by Stahl and Liu uncovered the stereochemical aspects of intramolecular aminopalladation under Wacker-type conditions. Here, the selectively deuterated compound 46 was used to probe the overall mechanism through product evaluation. It turned out that, for almost all common catalyst combinations, the reaction led to two deuterated alkenes, which were identified as product 47 and its regioisomer. As the final step of 3-hydride elimination must be a syn-selective... 

Reactions that are initiated by intramolecular aminopalladation have achieved considerable attention [6d]. This may be, first, due to the fact that this reaction provides access to a series of nitrogen heterocycles, which are important subunits in alkaloids, pharmaceuticals, and other molecules of biological interest Second, the resulting aUcyl-paUadium intermediate may undergo a range of subsequent reactions of further diversification making use of the whole portfolio of palladium-catalyzed reactions. The details on syn- and anti-aminopalladation have already been discussed in connection with Figure 16.1. 

Because intramolecular cyclization, in general, is entropically favorable, intramolecular aminopalladation of alkenes followed by Pd—H elimination appears to proceed well. However, the basicity of the amine again becomes a crucial factor. The first successful reaction of this type was carried out in 1976 by Hegedus et where less basic ary-... 

In summary, intramolecular aminopalladation, which has been studied extensively, compared to its intermolecular version, is undoubtedly useful for synthesizing N-heterocycles. Control of basicity and nucleophilicity of the N atom is crucial in this type of reaction. Considering such a fundamental feature, efforts will be directed toward the development of an asymmetric version of aminopalladation, which has not been studied much so far. 

Heating a DMA/pivalic acid solution of 6-(phenylamino)hex-2-ynoates in the presence of Pd(OAc)2 under an oxygen atmosphere gives pyrrolo[l,2-fl]indoles by a domino sequence involving intramolecular aminopalladation followed by C-H activation and reductive elimination (Scheme 141). ... 

A large number of nitrogen heterocycles can be synthesized by Pd -catalyzed cyclization of aminoalkenes. The first reported intramolecular aminopalladation of olefins mediated by Pd consisted of the cyclization of o-allylic anilines to 2-methylindoles. Both catalytic and stoichiometric procedures were developed using PdCl2(CH3CN)2 as catalyst (eq 14). This reaction features high yields, and tolerance toward functional groups and substitution on the allyl side chain. When the aniline substrate bears a methallyl side chain, palladium 8-hydride elimination is prevented and the cyclized alkylpalladium intermediate can be trapped by olefins in a Heck-type process (eq 15). Similar conditions have been used to convert o-amino styrenes into indoles. ... 

Intramolecular oxycarbonylation and aminocarbonylation are also known. As an example, frenolicin has been synthesized using oxycarbonylation at 1.1 atm of CO as a key step (eq 28). The intramolecular aminopalladation of a carbamate group and subsequent carbonylation of the substituted 3-hydroxy-4-pentenylamine proceeds smoothly in AcOH (eq 29). ... 

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